Although polychlorinated biphenyls (PCBs) and certain organochlorine pesticides induce liver tumors in animals, there is limited supporting epidemiologic data because of methodological challenges. There has also been little epidemiologic research into the risk associated with exposure to the low levels of aflatoxin, a known liver carcinogen, typically found in developed countries. We propose to investigate these relationships using already-collected serum and data from two large, population-based, prospective cohorts of men and women (total subjects =451,000) who provided blood samples and risk factor information between the mid- 1960s and mid-1970s. Follow-up and case ascertainment in these cohorts, one in Norway and one in Northern California, is very high and data on potential confounders are available. The aims of this study are to determine whether higher serum concentrations of organochlorines are related to increased risk of liver cancer;whether serum aflatoxin biomarkers are related to this risk;and if a synergy exists for these factors with each other or with HBV or HCV infection. We will include all cases of primary liver cancer diagnosed one or more years after blood draw (n=278) and a random sample of controls matched 3:1 to cases by cohort, age at blood draw, date of blood draw, sex, race, and county of residence (n =1,112 subjects total). We will measure serum concentrations of 39 PCB congeners, 11 organochlorine pesticides, and aflatoxin- albumin adducts, and assess HBV and HCV infection status using banked serum. We will also examine a second serum sample collected from a subset of subjects an average of 8 years after the primary sample. We will obtain information on potential confounders via linkage with previously collected health examination data (collected at blood draw), as well as clinical, census, and birth registry data available for each cohort. To our knowledge, this study would be the first to examine liver cancer risk in relation to body burden of PCBs. To be valid, such a study requires prospectively collected biospecimens because liver disease may affect the metabolism and subsequent elimination of organochlorines. The serum samples in this study were collected around the time that these organochlorines were banned in the U.S. and Norway and, thus, should reflect peak or near-peak levels of these chemicals in the general population of these countries. Although the production and use of these chemicals are banned in many countries, human exposure continues because of bioaccumulation in the food chain, ongoing use of organochlorine pesticides in less developed countries, leakage from equipment and landfills, and environmental persistence and redistribution. This study offers not only an efficient opportunity to examine the association of organochlorines and low-level aflatoxin exposure with risk of liver cancer, but also one of the few opportunities to study it in a methodologically rigorous way.